Association of Funisitis with Short-Term Outcomes of Prematurity: A Frequentist and Bayesian Meta-Analysis

The fetal systemic inflammatory response associated with intra-amniotic inflammation may play a key role in the pathogenesis of complications of preterm birth. Funisitis is the histologic equivalent of the fetal inflammatory response, whereas chorioamnionitis represents a maternal inflammatory response. We conducted a frequentist and Bayesian model average (BMA) meta-analysis of studies investigating the effects of funisitis on short-term outcomes of prematurity. Thirty-three studies (12,237 infants with gestational age ≤ 34 weeks) were included. Frequentist meta-analysis showed that funisitis was associated with an increased risk of any bronchopulmonary dysplasia (BPD), moderate/severe BPD, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), any sepsis, early-onset sepsis (EOS), and mortality. However, Bayesian meta-analysis showed that the evidence in favor of the alternative hypothesis (i.e., funisitis is associated with an increased risk of developing the outcome) was strong for any IVH, moderate for severe IVH and EOS, and weak for the other outcomes. When the control group was restricted to infants having chorioamnionitis without funisitis, the only outcome associated with funisitis was any IVH. In conclusion, our data suggest that the presence of funisitis does not add an additional risk to preterm birth when compared to chorioamnionitis in the absence of fetal inflammatory response.


Introduction
Preterm birth is a public health problem worldwide, with high rates of infant morbidity and mortality [1][2][3]. Intrauterine infection and/or inflammation are major contributors to the complications of very and extremely preterm birth (i.e., below 32 weeks of gestation) [4,5]. However, discerning between the part of the damage that is due to the infectious insult and the part related to the prenatal infection as a primary inducer of prematurity is a conundrum that continues to challenge perinatologists [4].
The systemic inflammatory response is an initially adaptive mechanism of the fetus to infection, but, when unregulated, it can lead to increased injury in the preterm infant [11,12].

Study Selection
The current study included observational studies reporting on the effects of funisitis in very and/or extreme preterm infants. Although the GA cutoff for this category of preterm infants is 32 weeks, studies that had an upper inclusion cutoff of 34 weeks were also included. Subsequently, a sensitivity analysis was performed to evaluate the effect of extending the inclusion limit to 34 weeks GA. Studies that included late preterm infants (GA ≥ 34 weeks) or that combined preterm and term infants were excluded. The primary outcome was short-term complications of prematurity, including mortality during first hospital admission, BPD, IVH, PVL, PDA, NEC, ROP, and sepsis.

Data Extraction, Definitions, and Risk of Bias Assessment
Data extracted included citation information, location of the research group, time period of study, study objectives, study design, inclusion and exclusion criteria, neonatal and maternal characteristics, data on funisitis, data on chorioamnionitis, and data on the different complications.
Risk of bias was assessed using the Newcastle-Ottawa Scale for cohort or case-control studies [20]. This scale assigns a maximum of 9 points (4 for selection, 2 for comparability, and 3 for exposure/outcome). Newcastle-Ottawa Scale scores ≥ 7 were considered as indicative of low risk of bias and scores of 5 to 6 as indicative of moderate risk of bias.

Statistical Analysis 2.4.1. Frequentist Meta-Analysis
Studies were combined and analyzed using COMPREHENSIVE META-ANALYSIS V3.0 software (Biostat Inc., Englewood, NJ, USA) [20]. Due to anticipated heterogeneity, summary statistics were calculated with a random-effects model. This model accounts for variability between studies as well as within studies [20,21]. Subgroup analyses were conducted according to the mixed-effects model. In this model, a random-effects model is used to combine studies within each subgroup, and a fixed-effect model is used to combine subgroups and yield the overall effect. The study-to-study variance (tau-squared) is not assumed to be the same for all subgroups. This value is computed within subgroups and not pooled across subgroups [20,21].
For dichotomous outcomes, the odds ratio (OR) with 95% confidence interval (CI) was calculated. For continuous outcomes, the mean difference (MD) or Hedges' g with 95% CI were calculated. When studies reported continuous variables as median and range or interquartile range, we estimated the mean and standard deviation using the method of Wan et al. and the calculator they provided [22]. Statistical heterogeneity was assessed by Cochran's Q statistic and by the I 2 statistic. I 2 was interpreted on the basis of Higgins and Thompson criteria, where 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively [23]. Potential sources of heterogeneity were assessed through subgroup analysis and/or random-effects (method of moments) univariate meta-regression analysis, as previously described [24]. For continuous covariates (examples: difference in mean gestational age between infants exposed and unexposed to funisitis), we used meta-regression analyses to test whether there was a significant relationship between the covariate and effect size, as indicated by a Z-value and an associated p-value. Metaregression coefficient indicates the change in the log of the OR of the association between mortality and the corresponding exposure for a unit change in the predictor covariate. Subgroups were compared using meta-regression for categorical covariates. For both categorical and continuous covariates, the R 2 analog, defined as the total between-study variance explained by the moderator, was calculated based on the meta-regression matrix. We used the Egger's regression test and funnel plots to assess publication bias. Subgroup analyses, meta-regression, and publication bias assessment were performed only when there were at least ten studies in the meta-analysis. A probability value of less than 0.05 (0.10 for heterogeneity) was considered statistically significant.

Bayesian Model Average Meta-Analysis
The results were further supplemented by a Bayesian model average (BMA) metaanalysis [25,26]. BMA employs Bayes factors (BFs) and Bayesian model averaging to evaluate the likelihood of the data under the combination of models assuming the presence vs. the absence of the meta-analytic effect and heterogeneity [25,26]. The BF 10 is the ratio of the probability of the data under the alternative hypothesis (H 1 ) over the probability of the data under the null hypothesis (H 0 ). The BF 10 was interpreted using the evidence categories suggested by Lee and Wagenmakers [27]: <1/100 = extreme evidence for H 0 ; from 1/100 to <1/30 = very strong evidence for H 0 ; from 1/30 to <1/10 = strong evidence for H 0 ; from 1/10 to <1/3 = moderate evidence for H 0 ; from 1/3 to <1 weak/inconclusive evidence for H 0 ; from 1 to 3 = weak/inconclusive evidence for H 1 ; from >3 to 10 = moderate evidence for H 1 ; from >10 to 30 = strong evidence for H 1 ; from >30 to 100 = very strong evidence for H 1 ; and >100 = extreme evidence for H 1 . Consequently, BMA allows us to distinguish the absence of evidence from the evidence of absence [28]. The BFrf is the ratio of the probability of the data under the random-effects model over the probability of the data under the fixed-effects model. The BFrf was interpreted in the following way: <1/100 = extreme evidence for fixed effects; from 1/100 to <1/30 = very strong evidence for fixed effects; from 1/30 to <1/10 = strong evidence for fixed effects; from 1/10 to <1/3 = moderate evidence for fixed effects; from 1/3 to <1 weak/inconclusive evidence for fixed effects; from 1 to 3 = weak/inconclusive evidence for random effects; from >3 to 10 = moderate evidence for random effects; from >10 to 30 = strong evidence for random effects; from >30 to 100 = very strong evidence for random effects; and >100 = extreme evidence for random effects. We used the empirical prior distributions based on the Cochrane Database of Systematic Reviews transformed to logOR; logOR~Student-t (µ = 0, σ = 0.78, ν = 5), tau = Inverse-Gamma (k = 1.71, θ = 0.73) [25,26]. We performed the BMA in JASP [29], which utilizes the metaBMA R package [30].

Description of Studies and Quality Assessment
The PRISMA flow diagram of the search process is shown in Supplementary Figure S1. Of 325 potentially relevant studies, 33 were included . These studies included 12,237 infants. Characteristics of the studies are summarized in Supplementary Table S1. Risk of bias assessment according to the Newcastle-Ottawa Scale is depicted in Supplementary Table S1. All studies received a score of at least six points, indicating a low to moderate risk of bias.

Main Meta-Analyses
Frequentist meta-analyses on the association between funisitis and short-term complications of prematurity (Fun+ vs. Fun−) are summarized in Figure 1. These metaanalyses showed an association between funisitis and odds of developing any BPD ( 15-4.72), and death before discharge (OR 1.58, CI 1.03-2.41). In contrast, funisitis was not significantly associated with severe BPD, severe ROP, PDA, cystic PVL, NEC, or LOS. As shown in Supplementary Table S2, exclusion of the seven studies that included infants with GA above 32 weeks but below 34 weeks [54,55,[57][58][59][60]62] did not significantly affect the results of the meta-analysis. As shown in Table 1, BMA analysis demonstrated that in the Fun+ vs. Fun− comparison, the evidence in favor of the alternative hypothesis was strong (BF10 from >10 to 30) for any IVH; moderate (BF10 from >3 to 10) for severe IVH and EOS; and weak (BF10 from 1 to 3) for mortality, any BPD, moderate/severe BPD, any ROP, severe ROP, PDA requiring treatment, PDA requiring surgery, any PVL, and any sepsis. Conversely, the evidence in favor of the null hypothesis was moderate (BF10 from 1/10 to <1/3) for cystic PVL and weak (BF10 from 1/3 to <1) for severe BPD, BPD or death, any PDA, any NEC, NEC ≥stage As shown in Table 1, BMA analysis demonstrated that in the Fun+ vs. Fun− comparison, the evidence in favor of the alternative hypothesis was strong (BF 10 from >10 to 30) for any IVH; moderate (BF 10 from >3 to 10) for severe IVH and EOS; and weak (BF10 from 1 to 3) for mortality, any BPD, moderate/severe BPD, any ROP, severe ROP, PDA requiring treatment, PDA requiring surgery, any PVL, and any sepsis. Conversely, the evidence in favor of the null hypothesis was moderate (BF 10 from 1/10 to <1/3) for cystic PVL and weak (BF 10 from 1/3 to <1) for severe BPD, BPD or death, any PDA, any NEC, NEC ≥ stage 2, NEC or death, and LOS. Data on heterogeneity of BMA analysis are depicted in Supplementary Table S3. When the control group included infants who had neither funisitis nor chorioamnionitis (Fun−/CA− group), frequentist meta-analysis showed an association between funisitis and odds of developing any BPD, moderate/severe BPD, any ROP, any IVH, severe IVH, any sepsis, EOS, and death before discharge. In contrast, frequentist meta-analysis could not demonstrate a significant association for severe BPD, BPD or death, severe ROP, PDA, NEC, PVL, or LOS ( Figure 2 and Table 2). BMA analysis of this comparison (Fun+ vs. Fun−/CA−) showed that the evidence in favor of the alternative hypothesis was strong (BF 10 from >10 to 30) for any PBD, any IVH, and severe IVH; moderate (BF 10 from >3 to 10) for mortality, any ROP, PDA requiring surgery, and EOS; and weak (BF 10 from 1 to 3) for moderate/severe BPD, BPD or death, severe ROP, any PDA, and PDA requiring medical treatment. Conversely, the evidence in favor of the null hypothesis was moderate (BF 10 from 1/10 to <1/3) for cystic PVL and weak (BF 10 from 1/3 to <1) for severe BPD, any PVL, any NEC, NEC ≥ stage 2, NEC or death, and LOS (Table 1).
When the control group included infants without funisitis but with chorioamnionitis (Fun−/CA+ group), the only outcome for which the positive association was maintained in the frequentist meta-analysis was any IVH (OR 1.58, CI 1.06-2.36) (Figure 2 and Table 2). BMA analysis showed that the evidence in favor of the alternative hypothesis was weak (BF 10 from 1 to 3) for any IVH and NEC or death. Conversely, the evidence in favor of the null hypothesis was moderate (BF 10 from 1/10 to <1/3) for mortality, BPD or death, PDA requiring medical treatment, PDA requiring surgery, severe IVH, and LOS; and weak for any BPD, moderate/severe BPD, severe BPD, any ROP, severe ROP, any PDA, any PVL, cystic PVL, any NEC, NEC ≥ stage 2, any sepsis, and EOS (Table 1).
Finally, we also conducted a meta-analysis including the three studies that differentiated grades or severities of funisitis [47,56,61]. As shown in Supplementary Table S4, this meta-analysis did not demonstrate an effect of funisitis grade on any of the outcomes.
Neither visual inspection of funnel plots (Supplementary Figure S2) nor Egger's test suggested publication or selection bias for any of the meta-analyses that include ten or more studies. Publication bias was not analyzed for meta-analyses including less than ten studies. Finally, we also conducted a meta-analysis including the three studies that differentiated grades or severities of funisitis [47,56,61]. As shown in the supplementary Table S4, this meta-analysis did not demonstrate an effect of funisitis grade on any of the outcomes.
Neither visual inspection of funnel plots (Supplementary Figure S2) nor Egger's test suggested publication or selection bias for any of the meta-analyses that include ten or more studies. Publication bias was not analyzed for meta-analyses including less than ten studies.

Additional Meta-Analyses and Meta-Regression
We conducted additional meta-analyses to investigate possible differences in baseline characteristics between infants with and without funisitis. As shown in Table 3, infants in the Fun+ group had significantly lower GA and BW than infants in the Fun− group. In addition, infants in the Fun+ group were more frequently female, were less frequently small for GA or had fetal growth restriction, were less frequently exposed to hypertensive disorders of pregnancy, and were less frequently born by cesarean section than infants in the Fun− group. All these significant differences were maintained when the Fun+ group was compared with the Fun−/CA− group (Table 3). In addition, infants in the Fun−/CA− group showed a lower rate of exposure to antenatal corticosteroids than infants in the Fun+ group (Table 3). In contrast, when the Fun+ group was compared with the Fun−/CA+ group, only the association with sex remained significant. That is, the Fun+ group included significantly more females than the Fun−/CA+ group (Table 3). In addition, three studies reported interleukin (IL)-6 levels in cord blood of preterm infants with funisitis. These levels were markedly elevated in the Fun+ group when compared to the Fun− group, the Fun−/CA+ group, or the Fun−/CA− group (Supplementary Table S5).
As described in our previous meta-analyses on chorioamnionitis [15][16][17][18][19], we conducted a meta-regression analysis to investigate the possible correlation between the difference in GA between the Fun+ group and the Fun− group and the effect size of the association between funisitis and outcome. This meta-regression analysis was only performed for the three outcomes (mortality, moderate/severe BPD, and any sepsis) that were reported in ten or more studies. As shown in Supplementary Table S6, none of these meta-regressions showed statistically significant results. In addition, the meta-regression also showed no significant correlation between the effect size of the association between funisitis-outcome and sex differences or differences in rate of exposure to antenatal corticosteroids (Supplementary Table S6).

Discussion
To the best of our knowledge, this the most extensive and comprehensive systematic review and meta-analysis that investigated the impact of funisitis, as a proxy of the fetal inflammatory response, on the risk of developing short-term complications of very preterm birth. Frequentist meta-analysis showed that funisitis was associated with an increased risk of any BPD, moderate/severe BPD, ROP, IVH, any PVL, any sepsis, EOS, and death before discharge. However, Bayesian meta-analysis showed that the evidence in favor of the alternative hypothesis (i.e., funisitis is associated with increased risk of developing the outcome) was strong for any IVH, moderate for severe IVH and EOS, and weak for the other outcomes that were significant (p < 0.05) in the frequentist meta-analysis. Interestingly, when the control group consisted of infants exposed to maternal inflammation but without fetal inflammation (i.e., chorioamnionitis without funisitis), the only outcome that remained significantly associated with funisitis in the frequentist meta-analysis was any IVH. Moreover, the Bayesian meta-analysis showed that the evidence in favor of this association was weak (BF 10 = 1.9). In addition, the Bayesian evidence in favor of an association between funisitis and complications, such as any BPD, severe IVH, any ROP, PDA requiring surgery, and EOS, becomes moderate-to-strong only when the control group consists of infants with neither fetal (i.e., funisitis) nor maternal (i.e., chorioamnionitis) inflammation. Therefore, our data suggest that the fetal inflammatory response does not add an additional risk to chorioamnionitis for most of the complications of prematurity. We speculate that that a significant part of the pathogenic effects of intrauterine infection/inflammation would be mediated by its role as a trigger of prematurity more than by the alterations induced in perinatal homeostasis.
The main limitation of our meta-analysis is the low number of studies reporting useful data to answer the research question. This is a very common problem in meta-analysis. In fact, a study published in 2011 showed that the median number of trials included in the meta-analyses from the Cochrane Database of Systematic Reviews was three, with an interquartile range from two to six [64]. Bayesian meta-analysis is increasingly being used to address the small-sample challenge [25,26]. In contrast to meta-analysis using frequentist statistics, Bayesian meta-analysis has the ability to quantify evidence in favor or against any hypothesis (including the null hypothesis), and to discriminate, therefore, between absence of evidence and evidence of absence [25,26,65,66]. This is a relevant advantage over the dichotomous interpretation of frequentist inference (significant vs. non-significant), particularly when p-values are close to the conventionally accepted limits (i.e., p < 0.05) [26,66,67]. This is clearly illustrated in Table 1 with the example of "any IVH". When the control group consisted of infants without funisitis or chorioamnionitis (Fun−/CA−), the association between funisitis and any IVH in the frequentist analysis was "highly significant" (p < 0.001). When the control group consisted of infants without funisitis but with chorioamnionitis (Fun−/CA+), the p-value (=0.026) of the frequentist meta-analysis was higher but still significant. By evaluation of BF 10 -values, Bayesian metaanalysis allows us to interpret that when the Fun−/CA− group was the control, the data were 65.6 times more likely under the presence-of-effect hypothesis in comparison to the effect-absence hypothesis. In contrast, when the Fun−/CA+ group was the control, the data were only 1.9 times more likely under the presence-of-effect hypothesis in comparison to the effect-absence hypothesis.
Our study did not include a Fun+/CA− group because isolated funisitis (i.e., without chorioamnionitis) is very uncommon (<5%) in preterm placentas [68][69][70]. In contrast, isolated funisitis is described in 17% of term placentas [68][69][70]. When histological examination of a placenta demonstrates both chorioamnionitis and funisitis, it is straightforward that a progressive intrauterine or intra-amniotic infectious process has occurred [70]. However, the clinical significance of isolated funisitis is less clear [70]. Potential explanations for isolated funisitis include a systemic transplacental infection, which affects the fetus but not the membranes. Alternatively, a sampling bias may occur if chorioamnionitis does not involve the entire chorioamniotic membranes [68]. In addition, isolated funisitis in term infants may occur due to damage to the cord resulting from meconium [70]. Interestingly, isolated funisitis in preterm infants is not accompanied by increased levels of cytokines in umbilical cord blood [68].
That the fetal inflammatory response induced by intrauterine infection may influence the outcome of prematurity is a biologically plausible hypothesis. The possible mechanisms linking perinatal inflammation/infection and complications of prematurity include (i) increased cardiopulmonary instability at birth with consequent higher requirement for respiratory and cardiocirculatory support and (ii) the potential pathogenic effects of hypoxia, acidosis, cytokines and other inflammatory mediators, as well as the increased ox-idative stress that accompanies infection and/or inflammation [71][72][73][74]. We confirmed these higher cytokine levels associated with funisitis (see Supplementary Table S5). Although this pathophysiological situation could theoretically affect any complication of prematurity, our data suggest that IVH is the outcome most strongly influenced by the presence of a fetal inflammatory response.
IVH generally occurs within the three first days of life and affects infants with higher hemodynamic and respiratory instability, frequently associated with extreme prematurity and/or severe perinatal infections [17,75,76]. Pro-inflammatory cytokines such as IL-6, IL-1β, and tumor necrosis factor (TNF)α can induce hemodynamic disturbances through direct vascular action or by the release of vasoactive mediators, like prostacyclin and nitric oxide [74]. In addition, cytokines can induce a neuro-inflammatory cascade in the fetal brain, which may promote platelet and neutrophil activation and adhesion leading to endothelial cell damage and changes in blood rheology and flow [77,78]. These changes, occurring inside the fragile germinal matrix capillaries or within the vascular connection between germinal matrix and the subependymal venous network, may increase the risk of developing IVH [17,[75][76][77][78]. However, it is noteworthy that our findings from the present meta-analysis did not encompass the more severe forms of IVH.
We have attempted to evaluate the effect of funisitis on various complications of prematurity, but it should be noted that all of these complications are multifactorial in their pathogenesis. Oxidative stress is one of the key pathogenic factors, but the causes of oxidative stress are also diverse [79][80][81][82][83]. Low GA is the main risk factor for any complication of prematurity. The development of antioxidant defenses is inversely proportional to GA, but, in addition, the more preterm infants are also the sickest. Therefore, they will have a greater need for aggressive mechanical ventilation and/or oxygen supplementation due to their more severe respiratory insufficiency [79][80][81][82][83]. Moreover, many of these infants will likely experience episodic hypoxia due to their underlying lung disease and clinical instability. They will also be more frequently exposed to postnatal infections, which increase the levels of reactive oxygen species (ROS), and to transfusions of adult erythrocytes. The latter increase the capacity of supplying oxygen to the tissues and augment the risk of iron overload and ROS generation through the Fenton reaction [79][80][81][82][83]. Additional sources of oxidative stress are parenteral nutrition [84] or phototherapy, which reduces the potential antioxidant capacity of bilirubin [85].
As mentioned above, GA is the main prognostic factor in preterm birth and as it decreases, mortality and morbidity increase. However, there is a growing awareness that, beyond GA, the pathophysiological pathway leading to prematurity plays a very relevant role in the outcome of prematurity [86][87][88][89]. The two main pathophysiological pathways, also termed endotypes, leading to very and extremely preterm birth are infection/inflammation and placental dysfunction [86][87][88][89]. Chorioamnionitis is the prototypical example of the infectious/inflammatory endotype. Numerous meta-analyses have demonstrated a robust association between chorioamnionitis and complications of prematurity, including BPD [15,90], ROP [16,91], IVH [17], PVL [92,93], NEC [94], EOS [18], LOS [18], and PDA [19,95]. However, for most of these outcomes, with the exception of IVH [17] and EOS [18], the effect of chorioamnionitis was strongly related to the fact that infants in the control group had significantly higher GAs than those in the chorioamnionitis group [15][16][17][18][19]. It is a well-known fact that the incidence of chorioamnionitis increases as GA decreases, and therefore the majority of extremely preterm newborns belong to the infectious/inflammatory endotype [7].
Our present data further suggest that fetal invasion (i.e., funisitis) occurs more frequently at lower GAs. Therefore, an undetermined component of the pathologic effect of funisitis may be related to this higher degree of prematurity rather than to the inflammatory stress that generates in the fetus. Nevertheless, while in our previous meta-analysis on chorioamnionitis [15][16][17][18][19] meta-regression showed a highly significant correlation between the lower GA of the chorioamnionitis group and the various complications of prematurity, this result could not be reproduced for funisitis (see Supplementary Table S3). However, it should be noted that the number of studies that could be included in the meta-regression was quite limited. The recommendation is to conduct meta-regression studies from a minimum of 10 studies per examined covariate [96,97] and our meta-regressions were just above that limit.
In addition to GA, infants with funisitis differ from those without funisitis in characteristics that may be critically relevant to the prognosis of prematurity, such as sex, exposure to antenatal corticosteroids, mode of birth, or exposure to other pregnancy complications. Some of these findings are not surprising since pregnancies complicated by the infectious/inflammatory endotype are less likely to be associated with fetal growth retardation, hypertensive disorders of pregnancy, or birth by cesarean section than pregnancies complicated by the placental dysfunction endotype [87][88][89]98]. However, an interesting finding of our meta-analysis is that funisitis was negatively associated with male sex. Although some studies had reported such sex differences [58,99], the finding was not consistent and there are cohorts in the literature in which male sex was associated with increased risk of funisitis as compared with female sex [100]. Interestingly, evidence from pre-clinical and clinical studies suggests that the male fetus exists in a relatively more pro-inflammatory environment than the female fetus [101]. As Challis et al., have pointed out, there is a growing need to consider fetal sex in studies of placental function and pathology [101]. In a recent meta-analysis, in which we investigated sex differences in pregnancy complications and outcomes of very preterm birth, we observed no difference in chorioamnionitis risk depending on fetal sex [102]. In contrast, hypertensive disorders of pregnancy were more frequent when the fetus was female [102]. There is a large body of evidence showing that boys are more susceptible than girls to adverse outcomes of prematurity, including BPD, ROP, NEC, IVH, chronic neurodevelopmental and cognitive impairment, and death [102][103][104]. Our group is currently conducting a meta-analysis focused on evaluating the possible effects of fetal sex on the different endotypes of prematurity and how these potential sex differences contribute to the male-female differences in prematurity outcome.
Antenatal corticosteroids in case of anticipated preterm delivery reduce infant mortality and morbidity and are the standard of care in current perinatal practice [105]. Our meta-analysis shows that the rate of use of antenatal corticosteroids is higher in preterm infants with funisitis when compared with infants who had neither funisitis nor chorioamnionitis (Fun−/CA− group). In a previous meta-analysis, we already observed that chorioamnionitis was associated with a higher rate of antenatal corticosteroid use. Paradoxically, clinical chorioamnionitis was considered for a time as a contraindication, at least relative, for the use of antenatal corticosteroids [106,107]. However, there is strong evidence that the positive effect of antenatal corticosteroids also applies to preterm infants with chorioamnionitis [108,109]. We speculate that the more frequent use of antenatal corticosteroids in the infectious/inflammatory endotype may be related to the availability of more time to prepare the fetus for preterm birth compared to the time available, for example, in hypertensive disorders of pregnancy that more often require an emergency cesarean section.
Our meta-analysis has several limitations that should be taken into account. First, as mentioned above, the number of studies for many of the outcomes analyzed was low and some of the meta-analyses had moderate or high heterogeneity. We attempted to overcome these limitations by means of the BMA meta-analysis. In addition, only three studies [47,56,61] reported a gradation of funisitis. Moreover, several studies did not report a clear definition of some of the outcomes, which made classification difficult. On the other hand, the main strength of the present study is the use of rigorous methods, including an extensive and comprehensive search and meta-analysis of baseline and secondary characteristics of the infants included in the studies.

Conclusions
In conclusion, our data suggest that funisitis is associated with an increased risk of relevant complications of prematurity, such as BPD, ROP, IVH, PVL, EOS, or death before discharge. However, infants with funisitis are also younger than infants without funisitis and part of the increased risk of complications may be related to this higher degree of prematurity. Moreover, with the exception of IVH, the presence of a fetal inflammatory response does not appear to add additional risk of complications when compared to chorioamniotic membrane inflammation without fetal involvement.
Supplementary Materials: The following supporting information can be downloaded at https://www. mdpi.com/article/10.3390/antiox12020534/s1: Figure S1. PRISMA Diagram; Figure S2. Publication bias; Table S1. Characteristics of the included studies and risk of bias assessment; Table S2. Metaanalysis on association between funisitis and short-term outcomes of prematurity in infants with gestational age up to 32 weeks; Table S3. Data on heterogeneity of the Bayesian model average (BMA) meta-analysis of the association between funisitis and outcomes of prematurity; Table S4. Meta-analysis on association between stages of funisitis and short-term outcomes of prematurity; Table S5. Meta-analysis on association between funisitis and levels of interleukin-6 in umbilical cord blood; Table S6. Meta-regression of the correlation between different covariates and the odds ratio of the association of funisitis with outcome of prematurity. Funding: This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Institutional Review Board Statement: As this systematic review and meta-analysis did not involve animal subjects or personally identifiable information on human subjects, ethics review board approval was not required.

Informed Consent Statement:
As this systematic review and meta-analysis did not involve animal subjects or personally identifiable information on human subjects, patient consent was not required.

Data Availability Statement:
All data relevant to the study are included in the article or uploaded as Supplementary Information. Additional data are available upon reasonable request.